Cyclic ethylene acetals of 3-acetoxy-2-formyl-5-oxocyclopentaneheptanoic acid

ABSTRACT

( + OR - )-Prostaglandin E1 is totally synthesized with a high degree of stereoselectivity and in good yield at the various steps from 6-methoxy-3-indanol by a sequence of reactions proceeding through 6-methoxy-3-indeneheptanoic acid ester, 2,6dioxo-4,5,6,7-tetrahydro-7-methyl-3-indanheptanoic acid ester 2cyclic ethylene acetal, cis-3,4,5,7a-tetrahydro-7-methyl-2oxoindanheptanoic acid ester, trans-trans 3-acetyl-2-(2-carboxyethyl)-5-oxocyclopentane heptanoic acid ester 5-cyclic-ethylene acetal, 3-acetoxy-2-formyl-5-oxocyclopentaneheptanoic acid ester 5-cyclic ethylene acetal, and 15-dehydro ( + OR - )-prostaglandin E1. The end compound has the biological activity of naturally occurring prostaglandin E1.

Enited States Patent 1191 Wendler et a1.

[75] Inventors: Norman L. Wendler, Summit; David Taub, lVletuchen, bothof NJ.

[73] Assignee: Merck & C0. Inc, Rahway, NJ.

[22] Eiled: Nov. 24, 11972 [21] Appl. No.: 309,389

Related US. Application Data [62] Division of Ser. No. 48,548, June 22,1970, Pat. No.

[52] US. 1111. 260/340.9; 204/158 R; 260/468 1F; 260/469; 260/473 F;260/488 B; 260/489 CD; 260/514 R; 260/520; 260/611 A;

[51] Int. (11 (C07d 131/04 [58] Field of Search 260/3409 [56] ReferencesEited UNITED STATES PATENTS 3,624,105 11 1971 Surmatis et al. 260/340.9

OTHER PUBLTCATIONS Pappo et al., Jour. Org. Chem., Vol. 21, 1956, pp.478-479.

Primary ExaminerDonald G. Daus Assistant Examiner.lames l-l. TurnipseedAttorney, Agent, or Firm-Thomas E. Arthur; l-lesna J. Pfeiffer; David L.Rose [57] AESTRACT (i)-Prostaglandin E is totally synthesized with ahigh degree of stereoselectivity and in good yield at the various stepsfrom 6-methoxy-3-indanol by a sequence of reactions proceeding through6-methoxy-3- indeneheptanoic acid ester, 2,6-diox0-4,5,6,7-tetrahydro-7-methyl-3-indanheptanoic acid ester 2- cyclic ethyleneacetal, cis-3,4,5,7a-tetrahydro-7- methyl-2-oxoindanheptanoic acidester, trans-trans 3- acetyl-2-(Z-carbbxy-ethyl)-5-oxocyclopentaneheptanoic acid ester. S-cycIic-ethylene acetal, 3-acetoxy-2-forrnyl-S-0xocyclopentaneheptanoic acid ester 5- cyclic ethylene acetal,and IS-dehydro (i)- prostaglandin E The end compound has the biologi calactivity of naturally occurring prostaglandin E 2 Claims, No DrawingsClr'CLlC ETHYLENE ACETAIJS OF 3-ACETOXY-2-FORMYL-5-OXOCYCLOPENTANEHEPTANOIC ACI CROSS REFERENCES TO RELATED APPLICATIONSThis is a division of application Ser. No. 48,548 filed June 22, 1970,now US. Pat. No. 3,736,335, issued May 29, 1973.

BRIEF SUMMARY OF THE INVENTION This invention relates to a new and noveltotal synthesis of (i) prostaglandin E and more particularly to a totalsynthesis that has a high degree of stereoselectivity at the points ofgenerating the asymmetric centers of the molecule. It relates further toa synthesis in which the yields are high in the several reaction steps.The invention relates further to the novel com pounds obtained asintermediates in the (i) prostaglandin E synthesis, and to the processesfor making such intermediates.

DETAILED DESCRIPTION OF THE INVENTION prostaglandin E, which may bedepicted structurally as t 45 is one of a group of naturally occurringcompounds known generally as prostaglandins. These prostaglandins haveinteresting and important biological activity, the precise biologicalproperties varying with the individual members of the prostaglandinfamily, as described in the article Prostaglandins, by I. W. Ramwell etal., Progress in the Chemistry of Fats and Other Lip- (CI-I COOIR 2 ids,Vol. IX, Polyunsaturated Acids, Part 2, pp. 231-273, Pergamon Press(1968).

One of the more important prostaglandins is prostaglandin E also knownas POE It has an effect on the contractility of smooth muscle and isuseful in the induction of labor in pregnant females and for thetermination of pregnancy by therapeutic abortion, M. I Embrey, BritishMedical Journal, 1970, 2, 256-258; 258-260. Other uses, besidesstimulation of smooth muscle, are described in the literature andinclude lowering of blood pressure, effect on mobilization of free fattyacids from adipose tissue, inhibition of lipolysis, and bronchodilatingeffect.

I'Ieretofore, the supply of prostaglandin E, as well as of otherprostaglandins, has been severely limited because only minute amounts ofnaturally occurring material are available, and partial biosynthesis byenzymes present in mammalian seminal vesicles has only afforded limitedamounts of the products.

Considerable effort has been directed to chemical synthesis of thesematerials (Axen, Synthetic Approaches To Prostaglandins, Ann. ReportsMed. Chem. 1967, pp. 290-296, Academic Press, 1968), but the synthesesavailable to date have suffered for the most part fromdisadvantages ofbeing only partial syntheses, lack of stereospecificity, or of affordinganalogs instead of the naturally occurring structures.

An object of this invention is to provide a stereoselective totalsynthesis of (i) prostaglandin E, which compound has one-half thebiological activity of the naturally occurring RGE and which may be usedfor the same biological effects as the natural compounds. This processobviates the disadvantages of the earlier synthetic processes since itis stereoselective, the individual reactions proceed in good yield, andit affords one of the naturallyoccurring prostaglandins.

A further object of the invention is to provide novel intermediatecompounds some of which, in addition to being useful in the synthesis of(i) PGE may themselves exhibit prostaglandin-like activity. Anadditional object is to provide a stereoselective total synthesis of theother members of the prostaglandin group which may be prepared by knownmethods from (5:) prostaglandin E Thus, for instance, (i) prostaglandinE may be obtained by reduction of (i) PGE Other objects will becomeevident from the following description of the invention.

The novel process and intermediates of our invention are shownstructurally in the following flow diagram, and immediately followingthis diagram the chemical names of the compounds are set forth.

(CH 3 Coca l 2 5 I ac (c 13 3? BL (QCE COOR (CEZ E COOH i i 2 steps \O nco 3,894,052 6 H c/pH (cn coon H\ orr (CH2;6COOH E e! W P H e 14 E i. =0

/ so no In the foregoing formulas the symbol 1R represents 18.3-acetoxy-2-(3-hydr0xy-1-octenyU-5- loweralkyl of about 1-6 carbon atomssuch as methyl, ethyl, propyl and hexyl.

As a matter of convenience for understanding the foregoing flowsheet andthe following description of the invention there follows a list of thechemical com pounds 1-20, inclusive.

1. -methoxy-3-indanol 2. (6methoxy-3-indanyl)triphenylphosphoniumbromide 3. 6-methoxy-A m -indanheptanoic acid methyl ester 4.6-methoxy-3-indeneheptanoic acid methyl ester 5.6methoxy-2-oxo-3indanheptanoic acid methyl ester 6.6-methoxy-2-oxo3-indanheptanoic acid, 2-cyclic ethylene acetal 7.2,6-dioxo-4,5,6,7-tetrahydro-3-indanheptanoic acid methyl ester,2-cyclic ethylene acetal 8. 2,6-dioxo-4,5,6,7-tetrahydro-7-methyl-3-indeneheptanoic acid methyl ester, 2-cyclic ethylene acetal 8a.4,5,6,7-tetrahydro-6-hydroxy-7-methyl-2-oxo-3-' indeneheptanoic acidmethyl ester, 2-cyclic ethylene acetal 8b.4,5,6,7-tetrahydro-6-hydroxy-7-methyl-2oxo-3- indeneheptanoic acidmethyl ester 8c. 2,4,5,6,7,7a-hexahydro-o-hydroxy-7-methyl-2-oxo-3-indeneheptanoic acid 9.2,4,5,6,7,7a-hexahydro-6-hydroxy-7-methyl-2- oxo-3-indeneheptanoic acidmethyl ester 10. cis-6-hydroxy-7-methyl-2-oxo-3- hydrindanheptanoic acidmethyl ester 1 1. cis-3,4,5,7a-tetrahydro-7-methyl-2- oxoindanheptanoicacid methyl ester 1 1a. cis-3,4,5,7atetrahydro-7-methyl-2-oxoindanheptanoic acid methyl ester, 2-cyclic ethylene acetal 12.3-acetyl2-( 2-carboxyethyl)-5- oxocyclopentaneheptanoic acid methylester, 5- cyclic ethylene acetal (cis-trans) 12a. 3-acetyl-2-(2-carboxyethyl)-5- oxocyclopentaneheptanoic acid methyl ester, 5- cyclicethylene acetal (trans-trans) 12b.3-acetyl-2-[2-(benzyloxycarbonyl)ethyl]-5-oxocyclopentaneheptanoic acidmethyl ester, 5-cyclic ethylene acetal 13.3-acetoxy-2-[Z-(benzyloxycarbonyl)ethyl]-5- oxocyclopentaneheptanoicacid methyl ester, 5- cyclic ethylene acetal 14.3-acetoxy-2-(2-carboxyethyl)-5- oxocyclopentaneheptanoic acid methylester, 5- cyclic ethylene acetal 15.3-acetoxy-2-vinyl-5-oxocyclopentaneheptanoic acid methyl ester, 5-cyclicethylene acetal 16. 3-acetoXy-2-formyl-5-oxocyclopentaneheptanoic acidmethyl ester, 5-cyclic ethylene acetal 17.3-acetoxy-2-(3-oxo-1-octenyl)-5- oxocyclopentaneheptanoic acid methylester, 5- cyclic ethylene acetal oxocyclopentaneheptanoic acid methylester, 5- cyclic ethylene acetal l9. 3-hydroxy-2-( 3-hydroxyl -octenyl)-5- oxocyclopentaneheptanoic acid, 5-cyclic ethylene acetal 20.3-hydroxy-2-(3-hydroxy-l-octenyl)-5-oxocyclopentane-heptanoic acid Inthe foregoing list of names the esters have been referred to as methylesters because the detailed examples refer to such esters, but it is tobe understood that other esters, and preferably loweralkyl esters, arewithin the scope of the invention as shown by the symbol R in the flowdiagram.

1n the first step of our invention 6-methoxy3-indanol is reacted with atrialkylphosphonium hydrobromide, or, preferably, triphenylphosphinehydrobromide in order to produce(6-methoXy3-indanyl)triphenylphosphonium bromide (Compound 2). Thereaction is conveniently carried out at about room temperature for from1 /2 to 3 hours in the presence of an organic solvent such as methylenechloride, chloroform, or tetrahydrofuran. The resulting product is nextreacted with a loweralkyl-6-formylhexanoate, such as methyl, ethyl orpropyl 6-formylhexanoate, in the presence of reagents suitable for usein a Wittig coupling reaction such as in a system comprising potassiumt-butoxide-dimethylsulfoxide, sodium hydride-dimethylsulfoxide or alkalimetal alkoxide-t-butanol or tetrahydrofuran. This reaction is alsoconducted at about room temperature and is generally substantiallycomplete in from 30-90 minutes. There is obtained a loweralkyl ester of6-methoXy-A m -indanheptanoic acid such as 6-methoxy-A -indanheptanoicacid methyl ester (Compound 3). This material is then isomerizeddirectly to 6-methoxy-3-indeneheptanoic acid methyl ester, or otherloweralkyl ester (Compound 4-), by contacting it with a strong acid insuitable solvent. Trifluoroacetic acid is the preferred isomerizationacid but others such as dilute aqueous hydrochloric acid orp-toluenesulfonic acid may be used if desired. Examples of solventswhich are suitable are chloroform, acetone, methanol, and benzene,acetone and methanol being used when hydrochloric acid is the catalyst.The time and temperature for the isornerization are not unduly critical,satisfactory results being obtained at room temperature in from about2-6 hours.

The 6-methoXy-3-indeneheptanoic acid methyl ester, or other loweralkylester, thus obtained is next converted to6-methoxy-2-oxo-3-indanheptanoic acid methyl ester, or other esters(Compound 5), by reacting it with osmium tetroxide in the presence of asolvent such as pyridine. The reaction is conveniently conducted atabout room temperature for from 12-24 hours and the resulting osmateester decomposed for from 12-24 hours and the resulting osmate esterdecomposed with reagents known for this purpose such as sodiumbisulfite. The resulting glycol is dehydrated to the ketone (Compound 5)by treatment with an acid such as p-toluenesulfonic acid,trifluoroacetic acid, or

hydrogen chloride in a suitable solvent such as benzene, methanol,dioxane, or chloroform.

Compound 5 is, in the next reaction sequence of the process of ourinvention, converted in two steps to 6- methoxy-2-oxo-3-indanheptanoicacid, 2-cyclic ethylene acetal (Compound 6). In the first of these twosteps the keto-ester Compound 5 is treated with ethylene glycol in thepresence of an acid catalyst such as p-toluenesulfonic acid in asuitable water-immiscible solvent such as benzene and the mixture heatedfor from 12-24 hours to afford the cyclic ethylene acetal. Water iscontinuously removed during the reaction. This latter product is thentreated with a strong base in an aqueous lower alkanol in order tosaponify the ester group and afford 6-methoxy-2-oxo-3-indanheptanoicacid, 2- cyclic ethylene acetal. As the base, there may be employedpotassium hydroxide or sodium hydroxide in a solvent such as methanol,ethanol or isopropanol.

In the next stage of the process of this invention 6-methxy-2-oxo-3-indanheptanoic acid; 2-cyclic ethylene acetal isconverted in three steps to 2,6-dioxo-4,5,6,7-tetrahydro-3-indanheptanoic acid loweralkyl ester, 2-cyclicethylene acetal (Compound 7). The first of these steps comprises theBirch reduction of Compound 6 preferably ,using lithium-liquid ammonia,although reagents such as sodium-liquid ammmonia or lithium-methylaminecould be employed if desired. The reduction is substantially complete inabout 3-5 hours at the reflux temperature of the preferred ammoniatetrahydrofuran-t-butanol solvent system. The resulting free acid isthen esterified with a diazoloweralkane to form a loweralkyl ester,suitable esters being methyl, ethyl and propyl. The methyl ester ispreferred and is frequently referred to hereinbelow, but it is to beunderstood that other loweralkyl esters may also be utilized equallywell throughout the synthesis. The diazoalkane esterification isconveniently brought about in ether at about room temperature for fromto minutes, utilizing a molar excess of the esterifying agent. Theresulting ester is then treated with aqueous acetic acid in the cold5l5C.) and the reaction allowed to proceed at this temperature for from4-7 hours. Although other weak acids such as propionic acid or aqueousoxalic acid may be used, the aqueous acetic acid system is preferred.The resulting 2,6-dioxo- 4,5,6,7-tetrahydro-3-indanheptanoic acid methylester, 2-cyclic ethylene acetal (Compound 7) is recovered by knowntechniques such as extraction into a waterimmiscible organic solventfollowed by removal of such solvent.

Compound 7 is next selectively methylated at the 7- position by formingan alkali metal enolate under aprotic conditions and then treating theenolate with methyl iodide. It is preferred to use lithiumtriphenylmethyl in a solvent system consisting ofhexamethylphosphortriamide and tetrahydrofuran as the enolating agentalthough the bromo magnesium enolate of acetomesitylene or any alkalimetal alkane that connot add to a carbonyl group such as sodiumtriphenylmethyl in ether, could be used, in each case methyl iodidebeing used to effect the desired methylation. The reactionproceeds'rapidly and satisfactory results have been obtained is from3-10 minutes at room temperature. At the end of the reaction period2,6-dioxo- 4,5,6,7-tetrahydro-7-methyl-3-indeneheptanoic acid methylester, 2-cyclic ethylene acetal or other loweralkyl ester (Compound 8)is recovered by extraction into a water-immiscible organic solvent and,if necessary, chromatographed over an adsorbent such as silica gel.

In the next reaction step of our invention, the 3- indeneheptanoic acidloweralkyl ester obtained as described immediately above is reduced withlithium tri-t- 'butoxy aluminum hydride, preferably in the cold, over aperiod of from 2-6 hours in order to convert the ketone at the 6position to a hydroxy group and produce 2-oxo-4,5 ,6,7-tetrahydro-6-hydroxy-7-methyl-3- indeneheptanoic acid loweralkylester, 2-cyclic ethylene acetal (Compound 8a). Other lithium trialkoxyaluminum hydrides, such as the trimethoxy, could also be used to reducethe ketone, as could sodium borohydride. A mixture of epimeric 6-hydroxycompounds is produced, and this mixture is carried through the reactionsequence until the 6-hydroxy group is removed in a later stage of ournovel process.

Upon completion of the foregoing reduction, the cyclic ethylene acetalblocking group at the 2-position is removed by reaction with an acidsuch as aqueous perchloric acid at temperatures from about 520C. for l-3hours to provide the free ketone (Compound 8b). Alternatively, aqueousacetic acid at elevated temperatures or aqueous hydrochloric acid in asolvent such as methanol at oven temperature could be employed toregenerate the ketone.

The ensuing reaction of our process comprises the isomerization of thedouble bond in Compound 8b to Compound 8c. This isomerization is broughtabout with a base such as sodium or potassium hydroxide in aloweralkanol, the reaction conveniently being carried out at about roomtemperature for from about 10-30 hours. During this step the loweralkylester is also saponified to the corresponding free acid, and it isnecessary to reform the ester for the ensuing transformations. The nextstep of the process, therefore, comprises re-esterification to afford2,4,5,6,7,7ahexahydro-6-hydroxy-7-methyl-2-oxo-3- indeneheptanoic acidloweralkyl ester (Compound 9). The esterification is brought about bytreating the free acid with a diazoalkane such as diazomethane ordiazoethane. It is preferred to produce the methyl ester usingdiazomethane in ether. Alternatively, the isomerization of Compound 8bto can be brought about by using an alkali metal alkoxide, preferablysodium methoxide, as the base in which case the ester group is not ceedssmoothly at about atmospheric pressure and room temperature, althoughhigher temperatures and pressures could be used, if desired. Thisreduction may 4 also be carried out on the free acid (instead of theester) and in this event the reduced product is esterified with adiazoalkane before proceeding with the next step of our process. Animportant and critical feature of this catalytic hydrogenation reactionis its stereospecificity since the product obtained (Compound 10) is inthe necessary cis configuration. It will be appreciated by those skilledin this art that this stereospecificity is essential at this stage ofour process in order to assure the proper orientation of the C-3 sidechain and the correct stereochemical course of subsequent reactions.

The next stage of our process involves introduction of a double bondbetween the 6 and 7 carbon atoms of the molecule. This is accomplishedby first reacting cis- 6-hydr0xy-7-methyl-2-oxo-3-hydrindanheptanoicacid loweralkyl ester (Compound 10) with a lowerallc anesulfonyl halideor a substituted phenylsulfonyl halide in the presence of an appropriateorganic base, and treating the resulting ester with dimethyl sulfoxideor sulfolane. lit is preferred to use a methanesulfonyl chloridepyridine system at O10C. to obtain the 6- mesylate derivative ofCompound 10, although satisfactory results can be obtained usingp-nitrophenylsul fonyl chloride or p-toluenesulfonyl chloride at roomtemperature in the presence of a base such as pyridine, a picoline, ortrimethylamine. The second reaction, i.e. of the 6-sulfonate withdimethyl sulfoxide or sulfolane is brought about at elevatedtemperatures of about 80100C. for from 210 hours, at the end of whichtime the desired product cis-3,4,5,7a-tetrahydro-7-methyl-2-oxoindaneheptanoic acid methyl ester, or other loweralkylester, (Compound 11) is recovered and purified by techniques known tothose skilled in this art such as extraction into and recovery from awater immiscible organic solvent and chromatography on a suitableadsorbent such as silica gel. in this reaction the heptanoic acid sidechain is isomerized to give predominantly the 3-exo isomer, which isimportant to the stereoselective nature of our total synthesis.

Prior to the next substantive step of our process the keto-ester(Compound 11) is converted to the corresponding cyclic ethylene acetal(Compound 11a) by reaction with ethylene glycol in the presence of anacid such as p-toluene sulfonic acid. The resulting acetal is thenoxidized with potassium permanganate preferably in the presence ofsodium periodate to produce the seco acid cis-trans3-acetyl-2-(2-carboxyethyl)-5- oxocyclopentaneheptanoic acid loweralltylester, cyclic ethylene acetal (Compound 12). if desired the sodiumperiodate can be omitted from this reaction system but such omissionrequires the use of larger quantities of potassium permanganate andtherefore is not a preferred aspect of the invention. The reactionproper affords predominantly the cis-trans isomer as depicted in theforegoing flow sheet as Compound 12. it is preferred, however, toconduct the oxidation in the presence of potassium carbonate. Thepotassium carbonate facilitates the reaction and incidentally partiallyepimerizes the cis-trans epimer to the more stable transtrans epirner sothat the immediate reaction product is a mixture of the two epimers.

in the next stage of this invention, the foregoing mixture of epirnersis reacted with an alkali metal alkoxide such as sodium methoxide orethoxide in a loweralkanol in order to complete the isomerization to thedesired trans-trans material (Compound 12a). The choice of alkoxide isnot critical, although it should correspond to the ester present inCompund 12 in order to avoid ester interchange. The reaction isconveniently carried out at about room temperature for from -20 hoursand the resulting trans-trans keto acid (Compound 121) then esterifiedwith phenyldiazomethane or a substituted phenyl diazomethane or asubstituted phenyl diazomethane to produce the corresponding benzylester 3-acetyl-2-[2-(benzyloxycarbonyl)ethyl]-5-oxocyclopentaneheptanoic acid loweralkyl ester, 5- cyclic ethyleneacetal (Compound 12b) which is required for the next substantivereaction.

The benzyl or substituted benzyl ester obtained as described above(Compound 12b) is treated with an organic peracid under Bayer-Villigeroxidation conditions to afford 3-acetoxy-2-[Z-(benzyloxycarbonyD-ethyl]-5-oxocyclopentaneheptanoic acid loweralkyl ester, 5-cyclicethylene acetal (Compound 13). It is preferred to use trifluoroperaceticacid as the oxidant although other peracids such as peracetic acid andm-chloroperbenzoic acid may be employed. The reaction mixture isbuffered with a weakly basic inorganic salt such as sodium bicarbonateor disodium hydrogen phosphate in order to preclude loss of the cyclicacetal radical. The reaction is preferably carried out at about roomtemperature for from 5-30 hours at the end of which time the desiredproduct is recovered by techniques known to those skilled in the art. itshould be noted that in this reaction the stereochemicai configurationat the center of oxygen insertion is retained, and correspondingly thatof the molecule as a whole.

The benzyl ester (Compound 13) is next subjected to hydrogenolysis toproduce 3-acetoxy-2-(2- carboxyethyl)-5oxo-cyclopentaneheptanoic acidloweralkyl ester, S-cyclic ethylene acetal (Compound 14). Thishydrogenolysis is conveniently carried out at atmospheric pressure andat about room temperature in the presence of palladium catalyst and in asuitably inert organic solvent such as ethyl acetate, ethanol, benzeneor dioxane.

Compound 14 is, in the next aspect of our process, oxidativelydecarboxylated to afford 3-acetoxy2-vinyl- 5-oxo-cyclopentaneheptanoicacid loweralkyl ester, 5- cyclic acetal (Compound 15) examples ofsuitable esters being the methyl, ethyl or propyl esters. This reactionis brought about by treating the starting material with leadtetraacetate in pyridine to induce formation of the lead salt of thecarboxylic acid, followed by copper acetate, and exposing this materialto irradiation with ultraviolet light in the range of 3,0003,500Angstrom units. The light in the range of 3,0003,500 Angstrom units. Thelight reaction is essentially complete in about l /24 hours at 25-35C.Alternatively, instead of ultraviolet light, the second phase of thisreaction may be effected by heating the mixture in benzene at about 80C.

The 2-vinyl compound (Compound 15) is then converted to thecorresponding 3-acetoxy-2-formyl-5-oxocyclopentanehpetanoic acidloweralkyl ester, 5-cyclic ethylene acetal (Compound 16) by reactionwith osmium tetroxide and sodium periodate in a solvent system such asaqueous tetrahydrofuran, aqueous ether or aqueous dioxane. it isnecessary to use only a catalytic amount of osmium tetroxide since thatreagent is continuously regenerated by the periodate which also cleavesthe glycol formed by osmium tetroxide. Satisfactory results are obtainedby carrying out the reaction at about room temperature for l to 3 hours.

In the next step of this process3-acetoxy-2-(3-oxo-loctenyl)-5-oxocyclopentane heptanoic acid loweralkylester, 5-cyclic ethylene acetal (Compound 17) is obtained by reactingtogether 3-acetoxy-2-formyl-5- oxo-cyclopentane heptanoic acidloweralkyl ester, 5- cyclic ethylene acetal (Compound 16) with adiloweralkyl-2-oxo-heptylphosphonate under Wittig conditions. it ispreferred to use a dimethyl or diethyl phosphonate but other dialkylphosphonates such as the di-m-propyl or dibutyl would be satisfactory.The reaction is carried out in the presence of sodium hydride at aboutroom temperature for 24 hours. Triphenyl or trialkylphosphonium yieldsmay be used in place of the dialkyl phosphonate but the latter ispreferred. The reaction is normally conducted in tetrahydrofuran,although other solvents such as dioxane or dimethoxy-ethane could beused if desired.

In the next reaction of our invention, Compound 17 obtained as describedabove as reduced with sodium borohydride to afford3-acetoxy-2-(3-hydroxy-loctenyl)-5-oxocyclopentaneheptanoic acid methylester, 5-cyclic ethylene acetal (or other loweralkyl ester) (Compound18) as a mixture of 2 epimers at the point of reduction. The reaction iscarried out in an inert solvent medium such as a loweralkanol ortetrahydrofuran, and potassium or calcium borohydride. The mixture ofepimers may be resolved at this stage of the process by chromatographyon silica gel, or the separation may be deferred until a subsequentpoint in the synthe- SIS.

In the preferred aspect of the invention, the mixture of epimersobtained immediately above (Compound 18) is treated with an alkali metalhydroxide such as sodium or potassium hydroxide in an aqueousloweralkanol to convert the loweralkyl ester (Compound 18) to thecorresponding free acid Compound 19. The saponification is convenientlybrought about at temperatures of from about 203SC. in about 2-4 hours.If desired, the epimeric mixture may be separated at this stage but ishas been found most convenient to defer the separation until after thenext reaction.

The final step of our stereospecific synthesis of (i) prostaglandin E,comprises removal of the cyclic ethylene acetal blocking group bytreating Compound 19 with aqueous acetic acid at a pH of from 4.5-5.5 ata temperature of from about l40C. Other acidic systems could be usedinstead of the aqueous acetic acid but they should be in the pH 4.5-5.5range since this pH control is important in order to retain the rest ofthe molecule intact on completion of the ketone regeneration. Thematerial thus obtained is chromatographed on silica gel and the morepolar material separated to afford (i)3-hydroxy-2-(3-hydroxy-1-octenyl)-5- oxocyclopentaneheptanoic acid, i.e.(i) prostaglandin E. This material possesses one-half of the biologicalactivity of the naturally occurring prostaglandin E,.

The following examples illustrate methods of carrying out the presentinvention but it is to be understood that these examples are given forpurposes of illustration and not of limitation.

EXAMPLE 1 (6-Methoxy-3-indanyl)-triphenylphosphonium bromide To a clear,stirred solution of 50 g. (0.3049 moles) of 6-methoxy-3-indanol in 750mls. of methylene chloride, contained in a 2-liter, single neck, roundbottom flask 102.3 g. (0.3049 moles) of triphenylphosphine hydrobromideare added in portions over 5 minutes. Stirring, at room temperature, ofthe clear yellow solution is continued for l hour.The reaction mixtureis then concentrated to dryness on the water pump yielding a rigid foam.i

250 Mls. of acetone are added to the foam. The foam dissolvescompletely, and almost immediately a white powdery solid starts toprecipitate. After the mixture is stirred for 30 minutes in an ice-bath,the solid is filtered, washed twice with cold acetone and partiallydried in air. The produce is dried in a vacuum over at 40C. to constantweight to afford 6-methoxy-3- indanyl-triphenylphosphonium bromide(Compound 2) as a white solid, mp. 2102l2C EXAMPLE 26-Methoxy-3-indeneheptanoic acid methyl ester To a stirred solution of9.625 g. of potassium tbutoxide in 60 ml. of dimethylsulfoxide is addeddropwise a solution of 40 g. of the phosphonium salt of Example 1 in 300ml. of dimethylsulfoxide. After 6 minutes an equimolar amount (12.93 g.)of methyl-6-formylhexanoate is added dropwise just discharing the redcolor of the reaction mixture. The mixture is stirred for 1 hour at roomtemperature, and then poured into 1 liter of ice-water and 350 ml. ofhexane. It is shaken, the white triphenylphosphine oxide is filtered offand the aqueous layer is extracted with ten ml. portions of hexane. Thecombined hexane extracts are succesively washed with four 250 ml.portions of (1:1) dimethylsulfoxide-water, four portions of water andone 300 ml. portion of saturated salt solution. After drying overmagnesium sulfate the hexane mixture is concentrated to a yellow oilcontaining 6-methoxy- A indanheptanoic acid methyl ester (Compound 3).The yellow oil is dissolved in chloroform (200 ml.) and to this is added5 drops of trifluoroacetic acid. The mixture is allowed to stand at roomtemperature for 4.5 hours and then concentrated to dryness in vacuo.Upon trituration with hexane (15 ml.) 6-methoxy-3- indeneheptanoic acidmethyl ester (Compound 4) separates in crystalline form, m.p. 303l.5C.

EXAMPLE 3 6-Methoxy-2-oxo-S-indanheptanoic acid methyl ester To 10.25 g.of 6-methoxy-3-indeneheptanoic acid methyl ester (Compound 4) in 40 ml.of dry pyridine 'is added at 15-l8C. with'stirring and cooling asolution of 9.0 g. of osmium tetroxide in 60 ml. of pyridine. Themixture is stirred at room temperature for 18 hours 'and added withstirring to a solution of 16.2 of sodium bisulfite in 270 ml. of waterand ml. of pyridine at about 18C. The mixture is allowed to warm to roomtemperature (25C.) and stirred for 1 hour. To this mixture is added 500ml. of chloroform and 500 ml. of water and the layers are shaken andseparated. The water level is extracted with four 250 ml. portions ofchloroform and the combined chloroform extracts extracted with ice cold2.5 N hydrochloric acid until the aqueous phase is pH'2. The chloroformlayer is washed successively with 5% sodium bicarbonate, water andsaturated salt solution, dried over MgSO, and concentrated to an oil invacuo. The glycol ester is used directly in the next step. 3

A solution of glycol ester from the previous step in 50 ml. of benzeneis added dropwise with stirring to a solution of 6.5 g. of anhydrousp-toluenesulfonic acid in 10 1 ml. of benzene. The mixture is stirred atroom temperature for 4 hours, decanted and the solid washed withbenzene. The combined benzene extracts are washed successively with 5%potassium bicarbonate, water and saturated salt solution, dried overMgSO and charcoal and concentrated in vacuo to an oil whichcrystallizes. The product is triturated with etherhexane (1:1) and driedto afford 6-methoxy-2-oxo-3-indanheptanoic acid methyl ester, m.p.33.5-35C.

EXAMPLE 4 6-Methoxy-2-oxo-3-indanheptanoic acid, 2cyclic ethylene acetalA. A mixture of 16.5 g. of 6-methoxy-2-oxo-3- indanheptanoic acid methylester,650 ml. of benzene, 24 ml. of ethylene glycol (24.0 ml.) and 0.36g. of p-toluenesulfonic acid in a flask equipped with a condenser andwater separator is heated with stirring to reflux under a nitrogenatmosphere. Reflux with stirring is continued for 22 hours at the end ofwhich the mixture is allowed to cool under nitrogen. The mixture ischilled to 6C., an excess of 5% aqueous potassium carbonate is added.The benzene layer is extracted successively with three 250 ml. portionsof water and one of saturated salt solution, dried over Na SO andconcentrated to an oil in vacuo. The total concentrate of 6-methoxy-2-oxo-3-indanheptanoic acid methyl ester, 2-cyclic ethyleneacetal is used directly in the next step.

B. The ester of the previous step is dissolved in 175 ml. of methanolunder nitrogen and a chilled solution of 5.3 g. of potassium hydroxidein 88 ml. of methanolwater (3:1) is added dropwise with stirring. Themixture is stirred for 2.5 hours and allowed to stand overnight at roomtemperature (25C.). The mixture is then concentrated to small volume invacuo, diluted with ice-water and extracted with two 60 ml. portions ofbenzenehexane (1:1).

To the aqueous phase is added 200 ml. of chloroform and then 10% aqueousmonosodium phosphate with stirring to pH 6. The water layer is extractedwith four 100 ml. portions of chloroform and the combined chloroformextracts extracted with one 200 ml. portion of water and one ofsaturated salt solution. The chloroform extract is dried over Na SOfiltered through 12 g. of silica gel and concentrated to an oil in vacuowhich is substantially pure 6-methoxy2-ox0-3- indanheptanoic acid,2-cyclic ethylene acetal by thin layer chromatography. This material isused directly in the following step.

EXAMPLE 5 2,6-Dioxo-4,5,6,7-tetrahydro-3-indanheptanoic acid methylester, 2-cyclic ethylene acetal 11.32 g. of the lcetal acid of Example 4is dissolved in 290 ml. of tetrahydrofuran and dry t-butanol (1:1) andthe solution is added dropwise with stirring and cooling to 290 ml. ofliquid ammonia. 4.045 g. of lithium wire is immersed in hexane to freeit from grease, then added in strips about 1.5 inches long to thereaction mixture with stirring. The addition takes place over 4 hoursduring which the mixture gently refluxes. After 15 minutes of additionalstirring 25 ml. of methanol is added to discharge the blue color,followed by 80 ml. more of methanol. Nitrogen is slowly passed over themixture to sweep out most of the ammonia over a period of 18 hours.

The mixture is diluted with 250 m1. of water and concentrated using anaspirator to remove ammonia, concentrated in vacuo to removetetrahydrofuran and tbutanol. 100 m1. of water is added to theconcentrate and the mixture is extracted with two 100 ml. portions ofether. To the alkaline aqueous layer is added with stirring 150 ml. ofcold chloroform and ice-cold 10% aqueous monosodium phosphate to pll-l5.5. The layers are separated and the water phase is extracted with fourml. portions of chloroform. The combined chloroform extracts are washedin turn with two ml. portions of water and one 200 ml. portion ofsaturated salt solution, dried over Na SO and concentrated to an oil invacuo. The product weighs 1 1.15 g. and is used directly in the nextstep.

To the oil from the previous step in 25 m1. of ether there is added dryethereal diazomethane until no bubbling is seen. After 15 minutes, withan excess of diazomethane present, the mixture is swept with nitrogenand then concentrated to an oil in vacuo. The product weights 11.3. g.and is used directly in the next step.

To 9.4 g. of the ketal ester obtained immediately above in 18 ml. oftetrahydrofuran is added dropwise at 10C. 108 ml. of acetic acid-water1:1 The stirring at 10C. is continued under nitrogen for 5.25 hours. Thereaction mixture is poured into an excess of icecold potassiumbicarbonate solution and the mixture extracted with three 300 ml.portions of benzenehexane (9:1). The benzene extracts are washedsuccessively once each with water and saturated salt solution, driedover Na SO and concentrated to dryness in vacuo to afford2,6-dioxo-4,5,6,7-tetrahydro-3- indanheptanoic acid methyl ester,2-cyclic ethylene acetal, ir(neat) 5.75, 5,82, 10.50;.t.

EXAMPLE 6 2,6-Dioxo-4,5,6,7-tetrahydro-7-methyl-3- indanheptanoic acidmethyl ester, 2-cyclic ethylene acetal This experiment is carried outwith dried twicedistilled hexamethylphosphortriamide (HMPT), anhydrousand peroxide-free tetrahydrofuran (THF) and under a nitrogen atmosphere.An ethereal solution of methyl lithium (25.0 ml., 2.004 M) isconcentrated to dryness and pumped in vacuo. Under nitrogen at 1 atm. 46ml. of the Tl-lF is added to 2.24 g. of triphenylmethane and theresulting solution is added under nitrogen to the previously preparedmethyl lithium at 05C. The methyl lithium dissolves in 45 minutes andthe solution oflithium triphenylmethyl is stirred for 3.5 hours at roomtemperature under nitrogen. The mixture is diluted with 46 ml. of dry,oxygen-free HMPT at 510C. and allowed to warm spontaneously to roomtemperature. The mixture is 0.486 N with respect to lithiumtriphenylmethyl.

2.684 G. of 2,6-dioxo4,5,6,7tetrahydro-3- indanheptanoic acid methylester, 2-cyclic ethylene ketal in 25 m1. of dry THF is placed undernitrogen and added dropwise at room temperature to a Well stirredsolution of lithium triphenylmethyl (16.03 ml., 0.486 N) prepared aspreviously described. The resulting mixture is added dropwise withstirring to 33 ml. of methyl iodide and the mixture is stirred for 5minutes at room temperature, poured into a mixture of 6 ml. of aceticacid, 50 m1. of benzene, 50 ml. of hexane and 10 ml. of water, andfinally neutralized with 5% aqueous potassium bicarbonate. The layersare separated, the water phase extracted with four 50 ml. portions ofhenzene and the combined benzene phases are extracted successively withfour 75 ml. portions of water and one of saturated salt solution. Thebenzene solution is dried over NA S0 and concentrated to dryness toyield 3.18 g. of 2,6-dioxo-4,5,6,7-tetrahydro-7methyl-3- indanheptanoicacid methyl ester, 2-cyc1ic ethylene ketal.

This product is dissolved in 30 ml. of chloroform and chromatographedover 32 g. of silica gel. Concentration of the product-rich fractionsaffords pure material nmr (CDC1 1.07 (d,3, J=7Hz), 3.40 (5,3), 3.58(s,4)

EXAMPLE 7 2,4,5,6,7,7a-l-lexahydro-6-hydroxy-7-methyl-2-oxo-3-indeneheptanoic acid methyl ester To 9.285 g. of2,6-dioxo-4,5,6,7-tetrahydro-7- methyl-3-indanheptanoic acid methylester, 2-cyclic ethylene ketal in 100 ml. of tetrahydrofuran undernitrogen, stirred at 0C. is added dropwise 13.5 g. of lithiumtri-t-butoxy aluminum hydride in 250 ml. of tetrahydrofuran. The mixtureis stirred at 0c. for 4 hours following which 100 ml. of saturatedaqueous sodium sulfate at 0C. is slowly added maintaining the mixture at0C. The mixture is concentrated in vacuo to remove tetrahydrofuran, theresidue filtered to remove salts and the aqueous phase extracted withethyl acetate. The organic phase is washed with saturated salt solution,dried and concentrated in vacuo to an oil (9.34 g.), of2-oxo-4,5,6,7-tetrahydro-6-hydroxy-7-methyl-3- indanheptanoic acidmethyl ester, 2-cyclic ethylene acetal which is used in the followingstep.

To the 9.34 g. of ketal ester obtained immediately above in 95 ml. oftetrahydrofuran is added aqueous perchloric acid (95 ml. 1.5 N) withstirring and cooling at 05C. The mixture is stirred at l015C. for 2hours, poured slowly into saturated aqueous potassium bicarbonate,filtered and the funnel washed with tetrahydrofuran. The filtrate isconcentrated in vacuo and the concentrate extracted with ethyl acetate.The combined organic extracts are washed with one-third volume ofsaturated salt solution, dried over MgSO, and concentrated in Vacuo toan oil, (8.37 g.) of 2-oxo- 4,5,6,7-tetrahydro-6-hydroxy-7-methyl-3-indanheptanoic acid methyl ester.

To this keto ester (8.37 g.) in 67.2 ml. of methanol under nitrogen andat C. is added dropwise with stirring a precooled solution of potassiumhydroxide (5.598 g. in 89.6 ml. of water and 58.2 ml. of methanol). Themixture is stirred at room temperature (C.) for 20 hours, concentratedin vacuo, extracted with three 50ml. portions of ether, cooled to 0C.,and l g. of monosodium phosphate added and the mixture acidified with2.5 N hydrochloric acid. The mixture is extracted with ethyl acetate,the combined organic extracts washed with saturated salt solution, driedover MgSO, and concentrated in vacuo to near dryness. The residue isflushed once with ether benzene (1:1) and concentrated in vacuo to anoil, (8.57 g.) of 2,4,5,6,7,- 7a-hexahydro-6-hydroxy-7-methyl-2-oxo-3-indeneheptanoic acid.

The ketol acid (8.57 g.) from the previous reaction is dissolved in 50ml. of ether and an excess of ethereal diazomethane is added at 0C.After minutes at 010C. the mixture is concentrated in vacuo to obtain8.93 g. of 2,4,5,6,7,7a-hexahydro-6-hydroxy-7-methyl-2-oxo-3-indeneheptanoic acid methyl ester as an oil which is usedwithout further purification. The A ketone has A CH Ol-l 239 mu, E13,500. I

EXAMPLE 8 Cis-6-hydroxy-7-methyl-2-oxo-3-hydrindanheptanoic acid methylester A vigorously stirred solution of 1.31 g. of 2,4,5 ,6,7,7-a-hexahydro-6-hydroxy-7-methyl-2-oxo-3- indeneheptanoic acid methylester in 50 ml. of ethanol is hydrogenated over 10% palladium oncharcoal at 1 atmosphere and 2025C. When the hydrogenation is completeas determined by disappearance of the 5.9 and 6.2 .t bands in the ir thecatalyst is removed by filtration, washed and the combined filtratesconcentrated to dryness in vacuo. The residue is chromatographed over 42g. of silica gel. Elution with 12% acetone in chloroform yieldscis-6-hydroxy-7-methyl-2- oxo-3-hydrindanheptanoic acid methyl ester, R0.2-0.3 on silica gel (12% acetone in chloroform).

EXAMPLE 9 Cis-3,4,5,7a-tetrahydro-7-methy1-2- oxoindanheptanoic acidmethyl ester A. To a stirred solution of 0.22 g. of 6-hydroxy-7-methyl-2-oxo-3-hydrindanheptanoic acid methyl ester in 1.5 ml. ofpyridine under nitrogen at 0C. is added dropwise a solution ofmethanesulfonyl chloride (0.740 g., 0.00647 mole) in 1 ml. of pyridine.The mixture is allowed to stand overnight at 0C., added to ice-water andafter 5 minutes extracted with four 25 ml. portions of ether. Thecombined ethereal extracts are washed successively with cold 1 Nhydrochloric acid, cold 5% potassium bicarbonate and saturated sodiumchloride, dried (MgSO, and charcoal) and concentrated to dryness invacuo. The 6-mesylate of the starting material is obtained as a nearlycolorless oil, (0.268 g.) R 0.3 on silica gel (1.5% acetone inchloroform) which is used directly in the next reaction. I

B. A solution of 0.268 g. of the mesylate ester obtained immediatelyabove in 3 ml. of dimethyl sulfoxide is maintained under nitrogen at C.for 7 hours. The mixture is then cooled to 5-l0C. and added to 50 g. ofice-water and extracted with four 50 ml. portions of hexane. The organicextract is washed successively with 4 portions of water of equal volumeand 1 portion of saturated salt solution; dried over MgSO andconcentrated .to an oil in vacuo. The residue is purified bychromatography on 20 g. of silica gel. 3,4,5,7a-Tetrahydro-7-methy1-2-oxoindanheptanoic acid methyl ester is eluted with2% acetone in chloroform. The yield is 0.1 l0g.'R 0.5 on silica gel (2%acetone in chloroform), ir (CHCl 1745 (C 0) and 1727 cm (ester C 0), nmr(CDCl 5.50 (m, l) 3.65 (s,

3), 1.67 (t, 3, J- 1.5 Hz) ppm.

EXAMPLE l0 3-Acetyl-2-[ 2-benzyloxycarbonyl )ethyl ]-5 oxocyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal bonate, the layersseparated and the aqueous phase extracted with benzene. The combinedbenzene extracts are extracted twice using equal volumes of saturatedsalt solution, dried over NaSO, and concentrated in vacuo to yield 0.58g. of the 2-cyclic ethylene acetal of the starting material, R 0.7 onsilica gel acetone in chloroform) ir (CHClg), 5,76,1050 ,u..

E. To a stirred solution of 0.375 g. of the immediately precedingproduct in 33 ml. of t-butanol under nitrogen at C. is added a mixtureof potassium carbonate (0.390 g.) sodium periodate (1.58 g.) andpotassium permanganate (0.018 g.) in 100 ml. of water. The mixture isstirred at 25C. for 20 hours, 0.4 ml. of ethylene glycol is added andthe mixture concentrated on a water pump until most of the t-butanol isremoved. A volume of water equal to the concentrate is added and themixture extracted with four ml. portions of benzene-ether (1:1) toremove neutral material. The aqueous layer is acidified with monosodiumdihydrogenphosphate and extracted with four 50 ml. portions of ethylacetate, dried over Na SO and concentrated to dryness to yield 0.320 g.of keto acid containing 3- acetyl-2-(2carboxyethyl)-5-oxo-cyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal. The latterproduct is dissolved in 3 ml. of anhydrous methanol and 1 ml. of 1.00 Msodium methoxide is added. The pale yellow mixture is kept undernitrogen for 17 hours, then-added to excess cold saturated aqueous sodium dihydrogenphosphate and extracted four times with ethyl acetate.The organic extract is dried over Na SO and concentrated to dryness togive trans keto acid (12a). To the latter in 5 ml. of ether is addedexcess ethereal phenyl diazomethane. The orange solution is kept at roomtemperature overnight. Benzene (5 ml.) is added, the mixture extractedwith dilute aqueous potassium bicarbonate, dried over sodium sulfate andconcentrated to dryness to give 3acetyl-2-[2-(benzyloxycarbonyl)ethyl]-5-oxocyclopentane heptanoic acid methyl ester,5-cyclic ethylene ketal. The latter is purified by chromatography on 20g. of silica gel, eluting with 7% acetone in chloroform: ir (Cl'rlCl5.77, 5.80, 5.83,10.55 u; nmr (CDCl 7.30 (s,5), 5.07 (s,2), 3.83 (s,4),3.60 (s,3), 2.09 (s,3) ppm.

EXAMPLE 1 l 3-Acetoxy2-[2-(benzyloxycarbonyl)ethyll-S-oxocyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetalBuffered peroxytrifluoracetic acid is prepared as follows: to 10 ml. ofmethylene chloride stirred at 0C. is added 1.08 ml. of 90% hydrogenperoxide. Trifluoracetic anhydride (7 ml.) is added over 23 minutes. Themixture is allowed to Warm to 2025C. and after 20 minutes is cooled to0C. Powdered disodium monohydrogen phosphate (7 g.) is added in portionswith good stirring. The reagent is kept at 0C. and by iodometrictitration is -0.3 Molar.

To 510 of 3-acetyl-2[2-(benzyloxycarbonyl)ethyl]-5-oxocyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene ketal in 6ml. of methylene chloride is added g. of Na MP0,. To the stirred mixtureat 0C. is added 5 ml. of the buffered 0.3 M peroxytrifluoracetic acid.The stirred mixture is kept at 25C. After 4 hours 4 ml. of 0.3 Mbuffered peroxytrifluoracetic acid is added and the mixture stirredovernight. An additional 4 ml. o'f0.3 Ml peroxytrifluoroacetic acid isthen added. After 24 hours total time the mixture is chilled, filteredand the precipitate washed with methylene chloride. The filtrate iswashed with aqueous sodium bisulfite, aqueous potassium bicarbonate,saturated aqueous sodium chloride, dried over sodium sulfate andconcentrated to dryness to give 520 mg. of 3-acetoxy-2-[2(benzyloxycarbonyl)ethyl]-5- oxocyclopentaneheeptanoic acid methylester, S cyclic ethylene acetal: ir(Cl-1Cl 5.75-5.80, 8.00, 10.55pm, nmr(CDCl 1.98 (s,3) ppm.

EXAMPLE l2 3-Acetoxy-2-(2-carboxyethyl)-5- oxocyclopentaneheptanoic acidmethyl ester, 5-cyclic ethylene acetal A solution of 4-75 mg. of3-acetoxy-2-[2(benzyloxycarbonyl)ethyl]-5-oxocyclopentaneheptanoic acidmethyl ester, 5-cyclic ethylene ketal in 5 ml. of ethyl acetate is addedto a pre-reduced suspension of 250 mg. of 10% Pd/C in 7 ml. of ethylacetate. Hydrogenation is carried out at 25C. and atmospheric pressure,and one molar equivalent of hydrogen is consumed in 20 minutes. Themixture is filtered, the precipitate washed with ethyl acetate and thefiltrate concentrated to dryness. The residue is dissolved in 20 ml. ofether, 20 ml. of hexane is added and the mixture extracted with aqueouspotassium bicarbonate. The latter extract is acidified with powderedNal-1 PO and extracted with ethyl acetate (4X30 ml.). The organicextract is dried over Na SO and concentrated to dryness to give 350 mg.of 3-acetoxy-2-(2-caboxyethyl)-5 oxocyclopentaneheptanoic acid methylester, S-cyclic ethylene acetal: ir(neat) 2.8-3.3, 5.78, 5.88, 8.10,110.55g.

EXAMPLE l3 3-Acetoxy2-vinyl5oxocyclopentaneheptanoic acid methyl ester,5-cyclic ethylene acetal To a solution of 380 mg. of 3-acetoxy-2-(2-carboxyethyl)-5-oxocyclopentaneheptanoic acid methyl ester 5-cyc1icethylene acetal in 12 ml. of benzene is added pyridine (240 mg.) Cu(OAc)11 0 (10 mg.) and lead tetraacetate (440 mg). Air in the system isdisplaced with nitrogen and the mixture is stirred in the dark for 30minutes. With continued stirring it is then photolyzed at 3500 A (tempabout 30C.) in a Rayonet photochemical reactor. After 2 hours ether andcold water are added followed by powdered Nail-l P0,. The mixutre isextracted with ether, the organic phase washed with water, diluteaqueous KHCQ and saturated aqueous NaCl. lt is dried over Na SC andconcentrated to dryness to give 210 mg. of 3-acetoxy-2-vinyl-5-oxocyclopentaneheptanoic acid methyl ester, S-cyclic ethyleneacetal. The product is purified by silica gel chromatography (20 g.)eluting with 7% acetone in chloroform: ir (CHCl 5.73, 5.77, 6.20, 8.00,10.55, 110.85 1" EXAMPLE 143-Acetoxy-2-formyl-5-oxocyclopentaneheptanoic acid methyl ester,5-cyclic ethylene acetal To a solution of 88 mg. of 3-acetoxy2-vinyl-5-oxocyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetal in2 ml. of tetrahydrofuran, stirred under nitrogen, is added 0.4 ml. of 1%aqueous osmium tetroxide (4 mg. Os0 Within 10 minutes the mixturebecomes black and 196 mg. of sodium periodate in 1.4- ml. of water isadded over 10 minutes. After 2 hours the mixture is filtered, theprecipitate of sodium iodate washed with ethyl acetate and the filtratewashed with saturated aqueous sodium chloride. It is dried over Na. Streated with charcoal, filtered, and the nearly colorless filtrateconcentrated to dryness to give 70 mg. of3-acetoxy-2-formyl-5-oxocyc1opentaneheptanoic acid methyl ester, -cyclicethylene acetal: ir 3.7, 5.77, 5.80, 10.55 1..

EXAMPLE l5 3-Acetoxy-2-( 3-oxol -octenyl )-5- oxocyclopentaneheptanoicacid methyl ester, 5-cyclic ethylene acetal 70 Mg. of dimethyl2-oxoheptylphosphonate in 2 ml. of tetrahydrofuran is added to 12 mg. of48% sodium hydride in 1 ml. of tetrahydrofuran, and the mixture stirredat 0C. under nitrogen for 30 minutes. 70 Mg.3-acetoxy-2-formy1-5-oxocyclopentaneheptanoic acid methyl ester,S-cyclic ethylene ketal in 2 ml. .of tetrahydrofuran is then addeddropwise and the mixture allowed to warm to 2025C. After 3 hours themixture is chilled, added to cold saturated aqueous NaH P0 extractedwith ethyl acetate, and the latter extract dried over Na SO andconcentrated to dryness. The residue is purified by silica gelchromatography (7.8 g. silica gel), eluting with 7% acetone inchloroform to give 3-acetoxy-2-( 3-oxol -octenyl )-5-oxocyclopentaneheptanoic acid methyl ester, 5-cyc1ic ethylene acetal: ir(CHCI 5.78, 5.9, 6.0, 6.17, 8.00, 10.55 p; U.V. A Cl-hOl-l 228 my. (EM10,050).

EXAMPLE l6 3-Acetoxy-2-( 3-hydroxyl -octenyl )-5-oxocyclopentaneheptanoic acid methyl ester, S-cyclic ethylene acetal Toa solution of 40 mg. of3-acetoxy-2-(3-oxo-loctenyl)-5-oxocyclopentaneheptanoic acid methylester, 5-cyclic ethylene ketal in 1.5 ml. of methanol stirred undernitrogen at 0C. is added 0.4 ml. of a solution of 17 mg. of sodiumborohydride in 2 ml. of methanol (3.4 mg. NaBl-1 After 30 minutes at 0C.the mixture is added to 20 ml. of cold saturated aqueous Nal-l,. P0 andextracted with ethyl acetate. The latter extract is dried over Na SO andconcentrated to dryness to give 40 mg. of3-acetoxy-2-(3-hydroxy-l-octeny1)-5- oxocyclopentaneheptanoic acidmethyl ester, 5-cyc1ic ethylene acetal as a mixture of hydroxy epimerson the octenyl side chain. If desired the epimers may be separated atthis stage by thin layer chromatography on silica gel (system 10%acetone in chloroform).

EXAMPLE 17 3-Hydroxy-2-(3-hydroxy-l-octeny1)-5 -oxocyclopentaneheptanoicacid, S-cyclic ethylene acetal To a stirred solution of 30 mg. of themixture of epimers of 3-acetoxy-2-(3-hydroxy-l-octenyl)-5-oxocyclopentaneheptanoic acid methyl ester, 5-cyclic ethylene acetalobtained in the preceding example in 1 ml. of methanol at 0C. undernitrogen is added 0.4 ml. of a solution of 88 mg. of potassium hydroxidein 1 ml. of water. The yellow solution is kept at 2025C. for 3 hours. Itis then added to cold saturated aqueous NaH PO4 (10 ml.) and extractedwith ethyl acetate. The latter extract is dried over Na SO4 andconcentrated to dryness to give 28 mg. of 3-hydroxy-2-(3- hydroxyl-octenyl)-5-oxocyclopentaneheptanoic acid, S-cyclic ethylene acetal as amixture of hydroxy epimers on the octenyl side chain. The substances areseparable on silica gel plates (systembenzene: dioxane: acetic acid:20:20:l), the most polar component (R 0.5) being the desired one.

EXAMPLE l8 3 -l-lydroxy-2-(3-hydroxy-1-octeny1)-5-oxocyclopentaneheptanoic acid (i) -prostaglandin E) A solution of 30 mg.of the epimeric mixture of 3- hydroxy-2-( 3-hydroxyl-octenyl)-5oxocyclopentaneheptanoic acid, 5-cyc1ic ethylene acetal in 2ml. of 50% aqueous acetic acid is kept at 2025C. for 3 hours. It is thenconcentrated to dryness to give 28 mg. of crude 3-hydroxy-2-( 3-hydroxyl-octenyl )-5- oxocyclopentaneheptanoic acid, (prostaglandin E Theproduct is purified by preparative thin layer chromatography on silicagel (system-benzene: dioxane: acetic acid 40:40:l) visualizing thecomponents by water spray. The band, which corresponds to prostaglandinE is eluted with methanol, the eluate filtered, the filtrateconcentrated to dryness and the residue taken up in chloroform. Thelatter solution is washed with aqueous NaH PO dried over Na SO andconcentrated to dryness. Crystallization of the residue fromether-hexane gives (i)-prostaglandin E m.p.-l 10C. The syntheticmaterial has identical tlc mobility as naturally derived prostaglandin EVarious changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of our invention.

What is claimed is:

- 1. 3-Acetoxy-2-formyl-5-oxocyclopentaneheptanoic acid lower alkylester, S-cyclic ethylene acetal.

2. The compound of claim 1 wherein the lower alkyl ester is the methylester.

1. 3-ACETOXY-2-FORMYL-5-OXOCYCLOPHENTANEHEPTANOIC ACID LOWER AKYL ESTER,5-CYCLIC ETHYLENE ACETAL.
 2. The compound of claim 1 wherein the loweralkyl ester is the methyl ester.